Project Summary Infant mortality is tracked annually worldwide. Knowledge of causes of infant mortality shapes public health policy and prioritizes diseases for investments in surveillance, intervention and medical research. As a result, rates of many causes of infant mortality have declined significantly over the past 50 years. The proposed research team has pioneered a new way to decrease infant morbidity and mortality associated with 14,000 genetic diseases, called genomic medicine: In it, genome sequencing can provide a genetic disease diagnosis in as little as 19 hours. Early genetic disease diagnosis in seriously ill infants allows empiric initial treatment to be replaced with specific evidence-based treatment for that condition. In 9 studies of 681 seriously ill children, genomic sequencing diagnosed 31%, 21% had consequent changes in treatment, and 13% had changes in outcome. As a result, genomic medicine is gaining broad acceptance in seriously ill infants. However, for genomic medicine to decrease infant morbidity and mortality maximally and to anticipate the value of genetic diagnoses, it is critical to determine the leading genetic causes of infant mortality in the context of other environmental factors. We propose to use genome sequencing and semi-automated interpretation to identify genetic diseases associated with 1,000 infant deaths in San Diego County between 2015 and 2022 and to evaluate potential environmental contributions to those same infant deaths. We will identify potentially preventable infant deaths by determining those deaths associated with specific genetic diseases for which targeted interventions are known to reduce mortality. This new knowledge will enable policymakers, researchers, and clinicians to prioritize those diseases for investments in new, life-saving interventions and treatments.